Rajkumar, S. Vincent

Introduction: There is a paucity of randomized trials to guide therapy for relapsed AL amyloidosis with treatment regimens generally extrapolated from experience in multiple myeloma. Methods: We conducted a retrospective review of patients who relapsed after receiving autologous stem cell transplant at Mayo Clinic. Patients treated for first relapse between January 2004 and December 2018 were included. Results: Three hundred and twenty-one patients were seen for relapsed AL amyloidosis post ASCT during the study period. Baseline characteristics were typical for a cohort with AL amyloidosis and are listed in Table1. 39% received therapy prior to transplant, conditioning in the majority (75%) was melphalan 200mg/m2. The median progression free survival from transplant (PFS1) was 30.7 months. Of the 321 patients 294 received treatment for relapsed disease. We categorized treatment regimens according to commonly used combinations and drug classes to further analyze outcomes. 34 patients were excluded from this analysis as they either proceeded directly to second ASCT (n=10) or received an atypical regimen not commonly considered for AL amyloidosis (n=24). Five categories of therapy regimens were identified, thalidomide based (n=110), melphalan plus steroids (n=31), 2nd generation immunomodulatory (IMiD) drug +/- alkylator (n=76), proteasome inhibitor (PI) +/- alkylator (n=116), PI plus IMiD (n=16), or daratumumab based (n=9). Disease and treatment characteristics for patients treated with these regimens are listed in Table 2. Patients treated with thalidomide had the shortest PFS1 (17.7 months) but PFS1 was similar for those treated with melphalan plus steroids, PI+IMiD and 2nd generation IMiDs (25.5, 24.3 and 25.6 months respectively). Patients treated with a PI +/- alkylator and daratumumab based regimen had the longest PFS1 (36.7 and 41.9 months respectively). The median duration of therapy was longer in patients treated with a 2nd generation IMiD or daratumumab based regimen (10.2, 12, 6.1, 5.5, 6.2 and 5.9 months for Dara based, 2nd generation IMiD, PI+/- alkylator, PI+IMiD, melphalan plus steroids and thalidomide based respectively). Hematologic response rate was lowest in those treated with melphalan plus steroids or thalidomide based regimens (44% and 55% respectively) and highest for patients treated with a PI+/- alkylator, (Figure 1). Progression free survival from relapsed therapy (PFS2) was longest amongst patients treated with daratumumab based regimens, PI +/- alkylator and 2nd generation IMiDs (not reached, 29.9 and 26.7 months respectively), Figure 2A. Overall survival from time of relapsed therapy favored patients treated with daratumumab based regimens, 2nd generation IMiDs and PI +/- alkylator, Figure 2b). Conclusion: A second generation IMiD based regimen or PI +/- alkylator produce high response rates and prolonged progression free and overall survival for relapsed AL amyloidosis. Patients treated with daratumumab based regimens and those treated with a PI plus IMiD also appear to do well, although numbers were low in our study. Patients treated with melphalan plus steroids or thalidomide based combinations have inferior outcomes and these regimens should be avoided. Disclosures Dispenzieri: Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Kapoor:Glaxo Smith Kline: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Janssen: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Gertz:Medscape: Consultancy, Speakers Bureau; Prothena Biosciences Inc: Consultancy; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Appellis: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; Annexon: Consultancy. OffLabel Disclosure: Daratumumab off label use for AL amyloidosis.

Introduction: Risk stratification of patients with light chain (AL) amyloidosis at diagnosis is invaluable. Currently, the Mayo 2012 staging system is mainly used to risk-stratify patients. We evaluated the role of increased mean corpuscular volume (MCV) at diagnosis in predicting survival. Methods: We conducted a retrospective study of patients with newly diagnosed AL amyloidosis seen at Mayo Clinic, Rochester between January 2006 through December 2015. The diagnosis of AL was confirmed with biopsy and the determination of organ involvement was according to consensus criteria. Staging was done according to the Mayo 2012 staging system and patients with stage III/IV were considered to have advanced stage disease. Patient and disease factors were compared for categorical and continuous variables using the χ2 and the Wilcoxon signed rank tests, respectively. Overall survival (OS) was defined as the time from diagnosis to death of any cause. Survival analysis was done using the Kaplan-Meier method. Results: A total of 1064 patients were identified and were divided into two groups: those with an MCV ≥ 96 fl (Elevated MCV, n=180) and those with an MCV <96 fl (Low MCV, n=884). The median age at diagnosis for the whole cohort was 64, with an interquartile range (IQR) of 57-71. Overall, 222 (23%) had Mayo 2012 stage 1, 199 (21%) had stage 2, 239 (25%) had stage 3, and 290 (31%) had stage 4 disease. Patients with an elevated MCV were more likely to be more than 65 years old compared to patients with a low MCV (61% vs. 44%, p<0.0001). They were also likely to have an advanced Mayo 2012 stage (68% vs. 53%, P=0.0008). The median OS was significantly lower in patients with an elevated MCV compared to patients with a low MCV (median PFS 13 months vs. 41 month, respectively, P<0.0001)(Figure 1). On a univariable analysis, predictors of OS were advanced Mayo 2012 stage (RR 3.26, P<0.001) and MCV ≥ 96 (RR 1.6, P<0.0001). On the multivariable analysis, both variables remained predictors of OS [advanced Mayo 2012 stage (RR 3.19, P<0.001) and MCV ≥ 96 (RR 1.3, P=0.016)]. Conclusion: The median OS was shorter by 28 months in newly diagnosed AL amyloidosis patients with an MCV ≥ 96 compared to patients with an MCV<96. An elevated MCV was predictive of shorter survival, independent of the Mayo Stage. This variable is easily available, measured in all newly diagnosed patients, and provides valuable prognostic information for the treating physician. Disclosures Dispenzieri: Intellia: Consultancy; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Akcea: Consultancy. Lacy:Celgene: Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Kapoor:Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Glaxo Smith Kline: Research Funding. Gertz:i3Health: Other: Development of educational programs and materials; Alnylam: Consultancy; Celgene: Consultancy; Appellis: Consultancy; Teva: Speakers Bureau; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Ionis/Akcea: Consultancy; Prothena Biosciences Inc: Consultancy; Janssen: Consultancy; International Waldenstrom Foundation: Research Funding; Proclara: Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; DAVA oncology: Speakers Bureau. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Introduction: Vitamin D deficiency is common, with 25-50% of the population having levels below the optimal range (<20 ng/mL). Aside from its role in maintaining serum calcium and skeletal homeostasis, vitamin D has been shown to play an important role in regulation of differentiation, proliferation, apoptosis, metastatic potential and angiogenesis in a variety of malignancies. Low serum 25(OH)D levels have been associated with a worse prognosis in several malignancies, including colorectal and breast cancer, chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Almost no data have been reported on vitamin D levels in light chain (AL) amyloidosis. We therefore measured vitamin D levels among AL patients and correlated levels at presentation to explore if vitamin D deficiency has any effect or association in this disease. Methods: Stored serum samples from 90 patients with newly diagnosed AL amyloidosis were obtained for vitamin D studies, which included 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D] and vitamin D binding protein (DBP). All vitamin D measurements were made by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Total 25(OH)D and 1,25(OH)2D was assessed as the additive sum of the 25(OH)D2/25(OH)D3 and 1,25(OH)2D2/1,25(OH)2D3 components, respectively. Clinical data was extracted from the electronic medical records. All calculations were made using JMP software (SAS, Cary, NC). Results: All patients were seen between June 2004 and September 2013. Median age was 63 [IQR 57-70]. Heart, kidney, nerve, liver and gastrointestinal amyloidosis was seen in 80%, 60%, 19%, 17% and 13% of patients, respectively. The median dFLC and bone marrow plasma cells were 28 (IQR 12-84) mg/dL and 10% (IQR 5-20%), respectively. The median serum 25(OH)D level was 20 ng/mL (IQR 10-29; normal >20 ng/mL), while the median serum level of 1,25(OH)2D was 23 pg/mL (IQR 14-37; normal 16-64 pg/mL for men; 16-78 pg/mL for women). 25(OH)D levels <20 ng/mL were strongly associated with renal involvement (84% renal involvement vs 42% of renal involvement for levels ≥20 ng/dL, P<0.001; Table). No other association with organ involvement was seen. Among all patients, heavy proteinuria (>5 gr/24-h) was strongly associated with low 25(OH)D, (P<0.001, Table). A weaker association was seen between 25(OH)D levels and estimated glomerular filtration rate (eGFR) (P=0.06). Seventy-eight percent of patients with 1,25(OH)2D levels below 20 pg/mL had renal involvement versus 48% in those with levels above 20 pg/mL (P=0.01). While heavy proteinuria was associated with 1,25(OH)2D (P=0.008), the association was stronger for eGFR, as no patient with an eGFR <30 ml/min/1.73 m2 had a 1,25(OH)2D level above 20 pg/mL (P<0.001). An association between vitamin D levels and low serum albumin was also seen, mainly in relation to 25(OH)D (Table). The median level of serum DBP was 58 μg/mL (IQR 36 - 120 μg/mL), significantly lower than the normal range (168-367 μg/mL). Low levels of 25(OH)D or 1,25(OH)2D were not associated with lower DBP levels. Surprisingly, patients with renal involvement had higher levels of DBP versus those without renal involvement (median 70.9 vs 48 μg/mL; P=0.03), although median levels were below normal in both groups. FISH data was available in 47 of patients (52%). Patients with 25(OH)D levels <20 ng/dL were less likely to harbor t(11;14) versus patients with 25(OH)D levels above this threshold (26% vs 64%, respectively; P=0.0095). A similar, but less significant association was seen between 1,25(OH)2D levels at a 20 pg/mL threshold and t(11;14) (35% vs 59%, P=0.09). Other associations between vitamin D and FISH abnormalities were not seen. Conclusions: Hypovitaminosis D is common among AL amyloidosis patients with renal involvement. In the general cohort, heavy proteinuria, reduced eGFR and low serum albumin were all associated with low circulating vitamin D levels. Although the majority of AL patients had low levels of DBP, urinary loss of DBP does not explain the low levels of vitamin D. Hypovitaminosis D is associated with non-t(11;14) disease, a finding which warrants further exploration. Disclosures Dispenzieri: Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Dingli:Rigel: Consultancy; Karyopharm: Research Funding; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Kapoor:Cellectar: Consultancy; Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Janssen: Research Funding; Glaxo Smith Kline: Research Funding. Leung:Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Russell:Imanis: Equity Ownership. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Gertz:Ionis/Akcea: Consultancy; Alnylam: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Annexon: Consultancy; Prothena Biosciences Inc: Consultancy; Spectrum: Consultancy, Research Funding.

Background: POEMS syndrome is a rare paraneoplastic syndrome caused by an underlying plasma cell disorder. The combination of a proteasome inhibitor, an IMiD and corticosteroid is known to be highly effective among patients with myeloma. Methods: We conducted a pilot using a 28-day oral regimen of ixazomib (4 mg days 1, 8, 15), lenalidomide (25 mg days 1-21), and dexamethasone (20 mg days 1, 8, 15, 22). Aspirin and acyclovir were used for prophylaxis. Eligibility included a diagnosis of POEMS syndrome, a plasma VEGF 2x normal, a PS < 3. There were two groups [gp] (intended enrollment 15 per gp): Gp 1, 3 cycles for pts destined for high-dose chemotherapy with stem cell transplant; Gp 2, 13 cycles for patients (pts) who had relapsed or refractory disease. Primary endpoint was VEGF complete response (CR=normalization) after 3 cycles. Secondary endpoints included safety, hematologic response, and overall survival at 3 and 12 months. Other domains including PET response (50% reduction in sum of SUVmax from baseline), clinical responses including neurologic response were also studied. Neurologic assessments were done using the modified neurological impairment score (mNiS+7POEMS), the overall neuropathy limitation scale, and the polyneuropathy disability score. To date, 13 pts enrolled since 10/31/2016-4 to Gp 1 and 9 to Gp 2. 11 pts were analyzed (2 dropped out before receiving any therapy). Data were frozen as of 07/15/2019. Results: Median age was 55; 73% were male. Of the evaluable patients, three were newly diagnosed (Gp 1), and 8 had relapsed or refractory disease (Gp 2). 72% met primary endpoint of VEGF CR (Table). At 3 months, the following improvements were seen: VEGF, 10/11; hematologic, 1/3; PET 1/3; neurologic impairment score, 3/11. By 12-months according to the modified nerve impairment scale, 3/6 had achieved objective improvement and 2/6 stable disease. With a median follow-up of 16 months, 2 patients have died of progressive disease and another patient progressed on therapy (Gp 2) with an extravascular leak progression. 27% of patients had grade 3+hematologic AE; 81% had grade 3-4 non-hematologic AE. These included: rash, respiratory infection, diarrhea, and hypotension in 2 each; atrial fibrillation, edema, dyspnea, and thromboembolism in 1 each. 5 pts had non-objective worsening of their neuropathy. Conclusions: These preliminary results suggest that Ixa-Len-Dex is an effective and tolerable regimen for patients with POEMS syndrome. Longer follow-up will be important to determine durability of this approach and for neurologic assessment given the slow rate of remyelination. Figure Disclosures Dispenzieri: Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Kapoor:Cellectar: Consultancy; Janssen: Research Funding; Glaxo Smith Kline: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Amgen: Research Funding. Leung:Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees; Omeros: Research Funding. Dingli:alexion: Consultancy; Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Gertz:Proclara: Membership on an entity's Board of Directors or advisory committees; Springer Publishing: Patents & Royalties; Research to Practice: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau. OffLabel Disclosure: No drugs approved for POEMS syndrome. Ixazomib, lenalidomide and dexamethasone

Background: A variety of risk factors have been described in multiple myeloma and current risk assessment incorporates ISS stage with specific FISH results and serum LDH (R-ISS). However, this model does not include all the current abnormalities described as prognostic for survival in multiple myeloma. Importantly, the impact of many of these high-risk abnormalities are not uniform. We examined if we can better integrate FISH results into a risk assessment tool to better predict the outcomes of newly diagnosed MM. Patients and methods: We studied a cohort of 1316 patients with FISH done within 6 months of diagnosis of MM, in whom results for commonly observed abnormalities were available. We specifically examined the individual impact of common translocations involving chromosome 14, MYC rearrangements, chromosome 1q gain (single or multiple duplication) and del13q/monosomy 13. A risk assessment system was developed, weighting each abnormality according to their Risk Ratio and integrating ISS stage and serum LDH into the final model construction. Overall survival was calculated from diagnosis, with those alive at last follow up being censored. Results: We first examined the impact of each of the above FISH abnormalities: 1) high risk translocations [t(4;14), t(14;16), or t(14,20)], 2) trisomies, 3) t(11;14), 4) MYCrearrangements, 5) del13q/monosomy 13, and 6) 1q gain . Each of the abnormalities, except for t(11;14), was prognostic for survival (Table 1 with the risk ratios). For 1q gain, the median OS was NR, 105 mos and 79 mos respectively for no abnormality, duplication of 1 copy and duplication of multiple copies, (p<0.001). On multivariate analysis, t(11;14) and trisomies were no longer prognostic for overall survival (Table 1). The cumulative impact of abnormalities demonstrated worsening survival in the presence of increasing numbers of abnormalities (Figure 1). Including ISS stage 3 and LDH > ULN as additional variables for prognostication indicated both were individually prognostic for OS. In a multivariate analysis, including these two and FISH abnormalities, 1q gain and LDH were not independently prognostic. The final model consisted of HR translocations, MYCrearrangements, del17p/monosomy 17, del13q/monosomy 13, and ISS stage 3. Each of these variables was weighted using their risk ratio and a composite score was developed using 998 patients for whom all variables were available (range: 0-7.9; median 1.8). Three patient groups were characterized: group 1 (0; 32%), group 2 (1-4; 58%) and group 3 (>4; 10%) with a median OS of 53 mos, 106 mos, and NR, respectively, p <0.001 (Figure 2). Conclusion: Using the most relevant FISH and laboratory factors, in a large cohort of patients, we refined the current system to develop a risk stratification system that predicts survival in patients with newly diagnosed MM treated with contemporary treatment regimens. This needs validation in future studies. Disclosures Kumar: Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Gertz:International Waldenstrom Foundation: Research Funding; Annexon: Consultancy; Medscape: Consultancy, Speakers Bureau; Amyloidosis Foundation: Research Funding; Abbvie: Other: personal fees for Data Safety Monitoring board; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Physicians Education Resource: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Appellis: Consultancy; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Amgen: Consultancy. Dispenzieri:Akcea: Consultancy; Janssen: Consultancy; Intellia: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Kapoor:Celgene: Honoraria; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Glaxo Smith Kline: Research Funding; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Cellectar: Consultancy. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Bergsagel:Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy.

Introduction: While the molecular target of immunomodulators such as pomalidomide (POM) and lenalidomide (LEN) has been identified, the mechanisms underlying therapeutic resistance remain incompletely understood. The uniformly emerging resistance to therapy over time in the absence of identifiable cereblon pathway mutations in the majority of patients raises questions about alternative mechanisms including aberrant gene expression. Methods: We performed gene expression profiling using an Affymetrix GeneChip Human Genome U133 Plus 2.0 microarray on CD138+ bone marrow cells from patients with relapsed / refractory (RRMM) and newly diagnosed (NDMM) multiple myeloma prior to initiating treatment. Patients were treated on two phase II clinical trial protocols (MC0789: POM ± dexamethasone in RRMM; MC0884: LEN ± dexamethasone in NDMM) between 2007 and 2012. We categorized patients based on their IMWG response as non-responders (SD) and responders (VGPR+). We selected 15 responders and 15 non-responders from MC0789 (n = 30) and compared overall survival, gene expression patterns, and involved cellular pathways between the two groups. We selected 5 responders and 5 non-responders from MC0884 (n = 10) for targeted validation of differentially expressed candidate genes. After data quality control and normalization of gene expression values, differential gene expression was estimated using limma. Statistical significance was adjusted for multiple testing in the discovery set using a false discovery rate-based approach for genome-wide experiments (q-value). We used Gene Ontology and PANTHER pathway analysis for functional annotation of differentially expressed genes. Overall survival estimates were calculated using the Kaplan-Meier method. Computation and visualization were performed in R. Results: Median age at treatment initiation on MC0789 was 65 years (40 - 82), 65% of the patients were male. Pomalidomide resistance was associated with an increase in mortality (median overall survival 1.6 versus 6.4 years, p = 0.009, Kaplan-Meier plot). There were 1076 differentially regulated genes between responders and non-responders (521 up- and 555 down-regulated, q < 0.050 for all genes, volcano plot). Expression of CRBN was 1.5-fold down-regulated in non-responders (q = 0.005). Supervised hierarchical clustering of the top 500 differentially expressed genes demonstrated distinct patterns in pomalidomide-resistant disease (heatmap). Gene ontology analysis revealed protein synthesis as one of the most enriched biological processes (bar graph). Pathway analysis showed a 6-fold enrichment (FDR = 0.007) of the ubiquitin proteasome pathway in pomalidomide-resistant disease. Differentially expressed genes involved key protein degradation pathways, epigenetic modifiers, and transcription factors. Targeted validation in MC0884 revealed 13 common genes with at least 1.5-fold differential expression (5 up- and 8 down-regulated), 12 of which have previously been implicated in the regulation of apoptosis, tumor glucose metabolism, Rho and Wnt signaling, miRNA-driven resistance to chemotherapy, and ubiquitin-dependent protein degradation (Table and Sankey diagram). The most up-regulated gene in non-responders was MYRIP, a gene coding for a vesicle trafficking protein associated with platinum resistance and suppression of pro-apoptotic BCL-2 family members in solid malignancies. The most down-regulated gene was FRZB, a gene coding for a negative regulator of Wnt signaling, previously implicated in the progression of monoclonal gammopathy of undetermined significance to multiple myeloma. Conclusions: Overall survival of patients with pomalidomide-resistant RRMM remains poor. Pomalidomide resistance was associated with differential gene expression in several potentially targetable cellular pathways beyond the known drug target cereblon. Targeted validation of candidate genes revealed common cellular pathways in immunomodulator-resistant disease. Elucidating the exact molecular mechanisms underlying immunomodulator resistance is of considerable interest for biomarker development and the identification of novel therapeutic targets and warrants further exploration. Figure Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Research Funding; Alnylam: Research Funding; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Akcea: Consultancy; Takeda: Research Funding. Kumar:Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Introduction: Recent advancements in the treatment of multiple myeloma (MM) have centered on engaging the immune system to target multiple myeloma cells. Although these therapies are being combined with immunomodulatory imide drugs (IMiDs) and corticosteroids, the individual contributions of these drugs on the immune system of MM patients has not been examined in the upfront setting. In this study, we examined the peripheral blood immunophenotypes of newly diagnosed multiple myeloma (NDMM) patients receiving the IMiD lenalidomide with or without the corticosteroid dexamethasone. Methods: To characterize immunophenotypes, we utilized flow cytometry to profile white blood cell populations from 35 patients enrolled in a clinical trial testing the efficacy of lenalidomide with and without dexamethasone in NDMM (NCT00772915). In this trial, all patients were initiated on single-agent lenalidomide. Dexamethasone was initiated in patients that did not meet desirable responses or for disease progression. At each cycle, peripheral blood was stained with a 17-marker antibody panel against several immune lineages and functional surface markers. We grouped patients into two groups: 1) lenalidomide alone or 2) lenalidomide with dexamethasone according to their treatment regimen at each cycle timepoint. Results: First we confirmed anti-myeloma cell activity for both groups by measuring a steady decline in circulating plasma cells in both groups. Examining peripheral blood immunophenotypes showed an expected decrease in T cells and a smaller decrease in B cells in both groups of patients. Closer inspection of B cell populations revealed a switch towards a more immature B cell phenotype in both treatment groups. This was measured as a switch from CD19-CD20+ cells to CD19+CD20- B cells. Inspection of T cell subsets revealed that patients receiving single-agent lenalidomide had a sustained decrease in the levels of CD4+ T cells and increase in the levels of CD8+ T cells. This was seen in both naïve and regulatory T cells evidenced by a decrease in the CD4/CD8 ratio among CD28+ T cells as well as CD25+ T cells. Importantly, this alteration did not lead to sustained alterations in the overall level of CD25+ or CD28+ T cells, and the addition of dexamethasone reverses this trend. In addition to the effects seen on T and B cell numbers, we detected expansions of NK cell populations in patients receiving lenalidomide alone. This expansion is detected as an overall increase in CD56+ mononuclear cells with the majority of cells being CD56+CD3- cells. Conclusions: Our data show that lenalidomide and dexamethasone therapy have shared but distinct effects on peripheral blood immunophenotypes in NDMM. Both drugs alter B cells numbers and populations leading to an expansion of CD19+CD20- B cells. However, lenalidomide alone decreases the CD4/CD8 T cell ratio; and, lenalidomide more strongly expands NK cell populations. The addition of dexamethasone reverses this trend and leads to a restoration of the CD4/CD8 ratio. This suggests that lenalidomide without dexamethasone might be counterproductive in immunotherapies intended to recruit CD4+ T cells. Conversely, lenalidomide alone could increase the efficacy of immunotherapies dependent on NK cell recruitment such as antibody-dependent cellular cytotoxicity (ADCC). This information may benefit future investigations of immune responses in MM patients and improve the adoption of immunotherapies to MM patients. Figure Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Background: Combinations of alkylating agents with proteasome inhibitors have demonstrated efficacy in newly diagnosed and relapsed multiple myeloma (MM), with melphalan or cyclophosphamide combinations being some of the commonly used regimens for initial treatment of MM. Ixazomib (Ixa) is an oral proteasome inhibitor that is approved for use in combination with lenalidomide for patients with relapsed MM. We examined if Ixa can be effectively combined with cyclophosphamide (Ctx) in order to develop a less expensive, all oral regimen for patients with relapsed MM. Patients and Methods: Patients with relapsed MM, who were proteasome inhibitor naïve OR have received less than 6 cycles of therapy with bortezomib and had a better than PR with no progression at the time of discontinuation, were enrolled. The primary objective was to determine overall response rate (ORR). Treatment consisted of Ixa 4mg PO days 1, 8, 15; Ctx 300 mg/m2 PO days 1, 8, 15, 22 and dexamethasone (Dex) 40 mg PO weekly in a 28-day cycle. Overall, 37 patients were accrued; data on 33 eligible patients were available for analysis as of July 18, 2019. Results: The median age was 71 (48-89), 61% were male and the median duration from diagnosis was 46 months (mos). Median number of prior lines of therapy was 4 (range 1-5), 76%, 42% and 67% respectively had a prior IMiD, proteasome inhibitor or stem cell transplant, respectively. At data cutoff, 22 (67%) had progressed, 4 (12%) had died and the median follow up of those alive was 21.3 mos. Fourteen patients are still receiving treatment, with median of 8.5 cycles. Most common reason for treatment discontinuation was disease progression (10 pts; 53%). The ORR was 60% including 6% CR and 24% VGPR. The median event free survival was 11.3 mos (95%CI: 9.0 - 26.8). Overall, 401 cycles have been administered across the study, with dose modifications/ hold required for Ixa, Ctx, and Dex in 9 (27%), 14 (42%), and 22 (67%) patients respectively, the most common reason being hematologic toxicity. A grade 3 or higher adverse event at least possibly attributed to the study drugs was seen in 77% of patients, hematologic in 67% and non-hematologic in 30%. (Table 1) The most commonly observed hematologic toxicities included thrombocytopenia, neutropenia, lymphopenia and anemia; for non-hematologic was nausea, diarrhea, peripheral neuropathy toxicity and fatigue. Conclusions: The combination of Ixa, Ctx and Dex (ICd) offers a convenient, all oral regimen for treatment of relapsed disease not refractory to proteasome inhibitors. The regimen has good efficacy in this group f heavily pretreated patients, with an acceptable toxicity profile. Disclosures Lacy: Celgene: Research Funding. Gertz:Ionis: Honoraria; Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria. Ailawadhi:Takeda: Consultancy; Janssen: Consultancy, Research Funding; Cellectar: Research Funding; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy. Bergsagel:Janssen Pharmaceuticals: Consultancy; Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy. Fonseca:AbbVie, Amgen, Bayer, Celgene, Kite, Janssen, Juno, Merck, Pharmacylics, Sanofi, Takeda: Other: Consultant/Advisor; Prognosticatin of MM based on Genetic Categorization by FISH: Patents & Royalties; Adaptive Biotechnologies: Other: Scientific Advisory Board. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Kapoor:Amgen: Research Funding; Takeda: Honoraria, Research Funding; Glaxo Smith Kline: Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding. Chanan-Khan:AbbVie: Research Funding; Pharmacyclics: Research Funding; Xencor: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding. Larsen:Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Russell:Imanis: Equity Ownership. Stewart:Roche: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; Ionis: Consultancy; Janssen: Consultancy, Research Funding; Oncopeptides: Consultancy; Ono: Consultancy; Amgen: Consultancy, Research Funding; Bristol Myers-Squibb: Consultancy; Celgene: Consultancy, Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Introduction: Waldenström macroglobulinemia (WM) is characterized by circulating monoclonal IgM and bone marrow infiltration with lymphoplasmacytic lymphoma (LPL) cells. Presently, there is limited data to guide prognosis or treatment options of WM based on the proportion of lymphocytes or plasma cells in the LPL population on the pathology. In this study, we aim to look at differing clinical features and outcomes of patients with WM based on the plasma cell (PC) percentage in the diagnostic bone marrow biopsy. Methods Patients with WM seen at Mayo Clinic, Rochester, MN between January 2001 and December 2017, with a bone marrow biopsy and a corresponding serum free light chain (FLC) examination at diagnosis of WM were included. The percentage of lymphocytes and PCs in the marrow biopsy was determined based on morphology ± immunohistochemistry. On immunohistochemistry, CD138 and/or MUM-1 positivity was used to quantify PCs, whereas CD20 and/or PAX5 were used to quantify lymphocytes. Patients with ≥10% PC component in the lymphoplasmacytic (LPL) cells on bone marrow biopsy were considered to have WM with excess plasma cells (WMEPC), while those with &lt;10% PCs were considered to have lymphocytic WM (LWM). Continuous variables were compared using Wilcoxon test and categorical variables were compared using Chi square test or Fisher's exact test. Time-to-next therapy (TTNT) was defined as the period from initiation of first line therapy to start of second line therapy or death due to any cause before second line therapy. Time-to-event analyses were conducted using Kaplan Meier method. Results: Of 228 evaluable patients, 147 (64%) had ≥ 10% PCs in the initial marrow biopsy. The median follow-up was 3.4 years (95% CI: 2.3-4.3 years) for LWM and 4.3 years (95% CI: 3.4-4.8 years) for WMEPC (p=0.33). The baseline characteristics of WMEPC versus LWM are depicted in Table 1. Patients with WMEPC had lower bone marrow involvement by LPL (30%) compared to LWM (60%; p&lt;0.001) at diagnosis, but the rate of symptomatic hyperviscosity was higher in WMEPC during the disease course (Table 1). The TTNT was shorter for WMEPC [2.6 years (95% CI: 1.8-4.5 years)] compared to LWM [4.5 years (95% CI 3.2-8.2)], although it did not reach statistical significance (p=0.09, Figure 1). There was a trend towards shorter OS for WMEPC [Not reached (95% CI 7.2- NR)] compared to LWM [10.7 years (95% CI 7.3 -12.1 years); p=0.28], Figure 2. Of the 228 patients, 79% (n=182) had data available for systemic therapy. The rate of PR or better with frontline therapy was higher in rates in LWM compared to WMEPC (61 % vs 42% p=0.02, Table 1). Among WMEPC cohort, patients receiving either a proteasome inhibitor (PI)-based or an immunomodulatory (IMiD)-based combination as frontline therapy (n=16) had higher rates of partial response or better (68%) compared to non-PI/non-IMiD based therapy (n=114), p=0.04. Conclusion: WM with excess plasma cells at diagnosis is associated with a trend towards shorter TTNT and OS compared to WM with &lt;10% plasma cells in the lymphoplasmacytic population at diagnosis. Our preliminary data shows higher rates of partial response or better with the use of PI/IMiD based therapy, but the small cohort size limits the strength of this finding which needs to be validated externally. Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding. Gertz:Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Alnylam: Honoraria; Ionis: Honoraria. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy. Lacy:Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Kapoor:Janssen: Research Funding; Cellectar: Consultancy; Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Honoraria.

Background: Multiple myeloma (MM) treatment has advanced considerably with proteasome inhibitors, immunomodulatory drugs (IMiDs), and, most recently, monoclonal antibodies. However, treatment response is quite heterogeneous, and many patients still progress even with novel combination therapies. Thus, understanding the factors that underlie response to treatment is a priority. Several somatic genomic aberrations and mutations predict poor response to therapy. However, germline variation has not previously been investigated as a predictor of treatment response in MM. We used genome-wide association and transcriptome-wide association approaches to identify germline genetic predictors of treatment response in MM. Methods: We included 510 MM patients from Mayo Clinic and 324 MM patients from UCSF diagnosed from 1999-2015. Basic demographics, laboratory values and pathology at diagnosis, type of initial therapy, duration of therapy, and follow-up were ascertained by chart review. Patients were grouped into categories of treatment based on their first line therapy: proteasome inhibitor-based regimen, IMiD based regimen, combination proteasome and IMiD based regimen, or other. Response was assessed using International Myeloma Working Group (IMWG) response criteria after 4-6 cycles of induction. As such, response was categorized into progressive disease (PD), minimal response (MR), partial response (PR), very good partial response (VGPR), or complete response (CR). Germline samples were genotyped using Illumina or Affymetrix arrays and were imputed based on the Haplotype Reference Consortium (HRC). For the genome-wide association study (GWAS), we included all SNPs with minor allele frequency >0.01 and imputation r2 of >0.5. We tested each SNP for association with treatment response using a linear regression model that adjusted for age, gender, and genetic ancestry (from principal components analysis (PCA)). To perform the transcriptome-wide association study (TWAS), we calculated predicted gene expression data using PREDIXCAN software on a reference cohort of 922 individuals with genotype and RNA expression data from peripheral blood. We then tested the association between predicted gene expression and response to therapy using linear regression models. Both the GWAS and TWAS were performed on subgroups of patients who received either proteasome inhibitors or IMiD therapies. The analyses of patients on proteasome inhibitors were adjusted for IMiD use as a covariate and analyses of patients on IMiDs were adjusted for proteasome inhibitor use. The threshold for genome-wide significance loci was set at P = 5 x 10-8 and the threshold for suggestive loci was set at P = 10-6. The threshold for significance for TWAS was set at P = 4 x 10-6 by using a Bonferroni correction for the number of genes for which genetic models of expression could be developed by PREDIXCAN. Results: Overall, 42.7% (59 of 138) of patients on proteasome inhibitors alone, 32.5% (66 of 203) of patients on IMiDs alone, and 58.1% (50 of 86) of patients on combination achieved at least a VGPR. There were no significant differences in response across centers in analyses that adjusted for age, sex and types of therapy. There were no genome wide significant loci to predict for response. We identified 8 suggestive SNPs associated with proteasome inhibitor response and 4 suggestive SNPs associated with IMiD response. TWAS identified ZNF622 as a candidate genetic modifier of proteasome inhibitor effect that was significant after correction for multiple hypothesis testing (P = 1.6 x 10-6). Higher genetically predicted expression was associated with improved response to proteasome inhibitor therapy. Among patients above the median of predicted expression of ZNF622 on proteasome inhibitors, 62.6% achieved at least VGPR; among patients at or below the median of expression, only 37.6% achieved at least VGPR. Conclusions: We identified an association between predicted expression of ZNF622 and clinical response to proteasome inhibitor therapy among MM patients. ZNF622 is a zinc finger binding protein which is known to be co-activator of B Myb activity and to affect apoptosis in response to oxidative stress. Our work highlights the potential importance of pharmacogenetic modifiers of treatment response in MM. Disclosures Shah: Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; University of California, San Francisco: Employment; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wong:Celgene: Research Funding; Janssen: Research Funding; Roche: Research Funding; Fortis: Research Funding. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding.